scholarly journals Epstein-Barr Virus Epitope–Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Anna Gil ◽  
Larisa Kamga ◽  
Ramakanth Chirravuri-Venkata ◽  
Nuray Aslan ◽  
Fransenio Clark ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Viral Infections ◽  
Cd8 T Cell ◽  
Barr Virus ◽  
Histocompatibility Complex ◽  
Tcr Repertoire ◽  
Epstein Barr ◽  
Selection Of

ABSTRACT Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse “de novo” clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1109 and BMLF1280, show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCRα CDR3 motifs played a dominant role, while TCRβ played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCRβ CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRα CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer. IMPORTANCE Several lines of evidence suggest that TCRα and TCRβ repertoires play a role in disease outcomes and treatment strategies during viral infections in transplant patients and in cancer and autoimmune disease therapy. Our data suggest that it is essential that we understand the basic principles of how to drive optimum repertoires for both TCR chains, α and β. We address this important issue by characterizing the CD8 TCR repertoire to a common persistent human viral infection (EBV), which is controlled by appropriate CD8 T cell responses. The ultimate goal would be to determine if the individuals who are infected asymptomatically develop a different TCR repertoire than those that develop the immunopathology of AIM. Here, we begin by doing an in-depth characterization of both CD8 T cell TCRα and TCRβ repertoires to two immunodominant EBV epitopes over the course of AIM, identifying potential factors that may be driving their selection.

scholarly journals CD8+ immunodominance among Epstein-Barr virus lytic cycle antigens directly reflects the efficiency of antigen presentation in lytically infected cells

2005 ◽  
Vol 201 (3) ◽  
pp. 349-360 ◽  
Author(s):  
Victoria A. Pudney ◽  
Alison M. Leese ◽  
Alan B. Rickinson ◽  
Andrew D. Hislop
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Lytic Replication ◽  
Lytic Cycle ◽  
E Proteins ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr ◽  
L Proteins

Antigen immunodominance is an unexplained feature of CD8+ T cell responses to herpesviruses, which are agents whose lytic replication involves the sequential expression of immediate early (IE), early (E), and late (L) proteins. Here, we analyze the primary CD8 response to Epstein-Barr virus (EBV) infection for reactivity to 2 IE proteins, 11 representative E proteins, and 10 representative L proteins, across a range of HLA backgrounds. Responses were consistently skewed toward epitopes in IE and a subset of E proteins, with only occasional responses to novel epitopes in L proteins. CD8+ T cell clones to representative IE, E, and L epitopes were assayed against EBV-transformed lymphoblastoid cell lines (LCLs) containing lytically infected cells. This showed direct recognition of lytically infected cells by all three sets of effectors but at markedly different levels, in the order IE > E ≫ L, indicating that the efficiency of epitope presentation falls dramatically with progress of the lytic cycle. Thus, EBV lytic cycle antigens display a hierarchy of immunodominance that directly reflects the efficiency of their presentation in lytically infected cells; the CD8+ T cell response thereby focuses on targets whose recognition leads to maximal biologic effect.

Dendritic Cells Expand Epstein Barr Virus Specific CD8+ T Cell Responses More Efficiently Than EBV Transformed B Cells

2005 ◽  
Vol 66 (9) ◽  
pp. 938-949 ◽  
Author(s):  
Marion Subklewe ◽  
Kathrin Sebelin ◽  
Andrea Block ◽  
Antje Meier ◽  
Anna Roukens ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Epstein Barr Virus ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr

scholarly journals Endogenous Presentation of CD8+ T Cell Epitopes from Epstein-Barr Virus–encoded Nuclear Antigen 1

2004 ◽  
Vol 199 (10) ◽  
pp. 1421-1431 ◽  
Author(s):  
Judy Tellam ◽  
Geoff Connolly ◽  
Katherine J. Green ◽  
John J. Miles ◽  
Denis J. Moss ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Antigen Processing ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Nuclear Antigen ◽  
T Cell Epitopes ◽  
Barr Virus ◽  
Degradation Rates ◽  
Epstein Barr

Epstein-Barr virus (EBV)–encoded nuclear antigen (EBNA)1 is thought to escape cytotoxic T lymphocyte (CTL) recognition through either self-inhibition of synthesis or by blockade of proteasomal degradation by the glycine-alanine repeat (GAr) domain. Here we show that EBNA1 has a remarkably varied cell type–dependent stability. However, these different degradation rates do not correspond to the level of major histocompatibility complex class I–restricted presentation of EBNA1 epitopes. In spite of the highly stable expression of EBNA1 in B cells, CTL epitopes derived from this protein are efficiently processed and presented to CD8+ T cells. Furthermore, we show that EBV-infected B cells can readily activate EBNA1-specific memory T cell responses from healthy virus carriers. Functional assays revealed that processing of these EBNA1 epitopes is proteasome and transporter associated with antigen processing dependent. We also show that the endogenous presentation of these epitopes is dependent on the newly synthesized protein rather than the long-lived stable EBNA1. Based on these observations, we propose that defective ribosomal products, not the full-length antigen, are the primary source of endogenously processed CD8+ T cell epitopes from EBNA1.

scholarly journals Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus.

1994 ◽  
Vol 180 (6) ◽  
pp. 2335-2340 ◽  
Author(s):  
V P Argaet ◽  
C W Schmidt ◽  
S R Burrows ◽  
S L Silins ◽  
M G Kurilla ◽  
...  
Keyword(s):  
T Cell ◽  
Persistent Infection ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Cytotoxic T Cell ◽  
Beta Chain ◽  
Memory Response ◽  
Barr Virus ◽  
Epstein Barr ◽  
Selection Of

To examine T cell receptor (TCR) diversity involved in the memory response to a persistent human pathogen, we determined nucleotide sequences encoding TCR-alpha and -beta chains from HLA-B8-restricted, CD8+ cytotoxic T cell clones specific for an immunodominant epitope (FLRGRAYGL) in Epstein-Barr virus (EBV) nuclear antigen 3. Herein, we show that identical TCR protein sequences are used by clones from each of four healthy unrelated virus carriers; a clone from a fifth varied conservatively at only two residues. This dominant selection of alpha and beta chain rearrangements suggest that a persistent viral infection can select for a highly focused memory response and indicates a strong bias in gene segment usage and recombination. A novel double-step semiquantitative polymerase chain reaction (PCR) procedure and direct sequencing of amplified TCR cDNA from fresh lymphocytes derived from three HLA-B8 individuals detected transcripts specific for the conserved beta chain in an EBV-seropositive donor but not in two seronegative donors. This report describes an unprecedented degree of conservation in TCR selected in response to a natural persistent infection.

scholarly journals Evidence for the Presentation of Major Histocompatibility Complex Class I–restricted Epstein-Barr Virus Nuclear Antigen 1 Peptides to CD8+ T Lymphocytes

2004 ◽  
Vol 199 (4) ◽  
pp. 459-470 ◽  
Author(s):  
Kui Shin Voo ◽  
Tihui Fu ◽  
Helen Y. Wang ◽  
Judy Tellam ◽  
Helen E. Heslop ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Epstein Barr Virus ◽  
Class I ◽  
Nuclear Antigen ◽  
T Cell Recognition ◽  
Barr Virus ◽  
Histocompatibility Complex ◽  
Epstein Barr

The Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) is expressed in all EBV-associated tumors, making it an important target for immunotherapy. However, evidence for major histocompatibility complex (MHC) class I–restricted EBNA1 peptides endogenously presented by EBV-transformed B and tumor cells remains elusive. Here we describe for the first time the identification of an endogenously processed human histocompatibility leukocyte antigen (HLA)-B8–restricted EBNA1 peptide that is recognized by CD8+ T cells. T cell recognition could be inhibited by the treatment of target cells with proteasome inhibitors that block the MHC class I antigen processing pathway, but not by an inhibitor (chloroquine) of MHC class II antigen processing. We also demonstrate that new protein synthesis is required for the generation of the HLA-B8 epitope for T cell recognition, suggesting that defective ribosomal products (DRiPs) are the major source of T cell epitopes. Experiments with protease inhibitors indicate that some serine proteases may participate in the degradation of EBNA1 DRiPs before they are further processed by proteasomes. These findings not only provide the first evidence of the presentation of an MHC class I–restricted EBNA1 epitope to CD8+ T cells, but also offer new insight into the molecular mechanisms involved in the processing and presentation of EBNA1.

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